Synthesis of <i>S</i>- and <i>N</i>,<i>S</i>-Heterocycle–Dipeptide Conjugates for Supramolecular Hydrogel Formation
Small peptides with aromatic nuclei at the <i>N</i>-terminus have been shown to form bioactive, biocompatible, and biodegradable supramolecular peptide hydrogels. Novel heterocycle–dipeptide conjugates with potential biological activity or application as drug carriers were synthesized by...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/4/869 |
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| Summary: | Small peptides with aromatic nuclei at the <i>N</i>-terminus have been shown to form bioactive, biocompatible, and biodegradable supramolecular peptide hydrogels. Novel heterocycle–dipeptide conjugates with potential biological activity or application as drug carriers were synthesized by using <i>S-</i>(benzo[<i>b</i>]thiophene) and <i>N</i>,<i>S-</i>(thieno [2,3-<i>b</i>]pyridine and thieno[2,3-<i>b</i>]quinoline) heterocycles as <i>N</i>-protective groups for dipeptides <span style="font-variant: small-caps;">l</span>-Phe-<span style="font-variant: small-caps;">l</span>-Phe and <span style="font-variant: small-caps;">l</span>-Phe-<span style="font-variant: small-caps;">l</span>-Leu. The synthesis involved coupling heterocyclic carboxylic acids with trifluoroacetate salts of ethyl <span style="font-variant: small-caps;">l</span>-phenylalanyl-<span style="font-variant: small-caps;">l</span>-phenylalaninate and ethyl <span style="font-variant: small-caps;">l</span>-phenylalanyl- <span style="font-variant: small-caps;">l</span>-leucinate using HBTU and Et<sub>3</sub>N, producing the corresponding six <i>N</i>-heterocycle–dipeptide ester conjugates, which were then hydrolyzed to the carboxylic acids. These conjugates were subjected to gelation tests in water starting from 0.4 wt% concentration of the conjugates, using a pH-lowering method with GdL. Among them, only the conjugate of benzo[<i>b</i>]thiophene with <span style="font-variant: small-caps;">l</span>-Phe-<span style="font-variant: small-caps;">l</span>-Phe-OH formed a hydrogel, with a gelation critical concentration of 0.15 wt% (GdL 0.6%) and a final pH of 6.8, which is important for biological applications. The hydrogel was characterized by STEM, revealing nanofibers with an average thickness of 17 nm that assemble into a 3D network capable of trapping water. Further rheological analysis demonstrated its viscoelastic behavior (G′ = 3.03 × 10<sup>3</sup> Pa; G″ = 3.28 × 10<sup>2</sup> Pa), comparable to the extracellular matrix of certain human tissues, crucial for biomedical applications. |
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| ISSN: | 1420-3049 |